Understnding Prudent Use Of Antimicrobials

John T. Waddell, DVM

Fri, 1999-04-30 12:00

Antimicrobial resistance in animal agriculture concerned mainly veterinarians and producers. That changed when the link was made between the resistance in animal and human pathogens.Before that link, concern was for continued effectiveness of the few antibiotics approved for use in food-producing animals. The potential economic effect also had a direct impact on how veterinarians and producers viewed

Antimicrobial resistance in animal agriculture concerned mainly veterinarians and producers. That changed when the link was made between the resistance in animal and human pathogens.

Before that link, concern was for continued effectiveness of the few antibiotics approved for use in food-producing animals. The potential economic effect also had a direct impact on how veterinarians and producers viewed antimicrobial resistance.

The animal-human antibiotic resistance link, and the potential effect on human health, has created a new, much more emotionally charged issue.

The worldwide emergence of resistance in foodborne and human pathogens has led the World Health Organization (WHO) to make the issue a top priority.

Defining Prudent Use of Antimicrobials WHO defines prudent use as that which "maximizes therapeutic effect of the antimicrobial agent while minimizing the development of antimicrobial resistance."

An industry-wide task force altered that definition of "prudent" use to exclude the portion of the WHO definition concerning resistance. The task force cited a lack of data identifying patterns of use which reduce the selection for resistant organisms in a clinical setting.

The task force definition of prudent use is "use that provides the desired therapeutic effect." The task force uses the term therapeutic as defined by the Food and Drug Administration's (FDA) Center for Veterinary Medicine (CVM) to include treatment, control and prevention of microbial diseases. These definitions, in their strictest sense, might preclude the use of all subtherapeutic or production enhancement antimicrobials unless their use could be considered control or prevention.

WHO and the Centers for Disease Control (CDC) both have a strong bias toward the human side of this discussion, preferring to see subtherapeutic uses of antibiotics banned. Their logic, "when in doubt, don't" says: "A risk has been identified. Potential risk has not been quantified. Why not err on the side of caution?"

What is overlooked in this scenario is the risk of removing antibiotics from food production and the resulting degradation of food safety. Is food produced with the benefit of antimicrobials actually safer and more wholesome than food produced without those benefits? The data to support this theory is as lacking as the data that refutes it.

What we do know is that therapeutic and subtherapeutic antibiotics still work. Especially in swine production, there continues to be ample supportive data for the use of antimicrobials for therapeutic as well as subtherapeutic applications. For years, antibiotics have demonstrated their efficacy in terms of welfare, economic and food safety benefits - and they continue to do so.

The definition of prudent use suggested by the task force, follows principles to promote efficacy, while at least theoretically minimizing thechance for resistance to develop. They suggested that therapeutic antimicrobial use be guided by the following simple principles:

For proven clinical indications - only when indicated - at the appropriate dosage regimen,

For as long as necessary and

For as short duration as possible.

Antimicrobial Resistance Antimicrobial resistance is the ability of certain bacteria, normally destroyed by antibiotics, to survive exposure to that antimicrobial. Doctors prescribe antibiotics that are known to kill or inhibit growth of specific bacteria causing a particular disease.

Many bacteria, however, are naturally insensitive to some antibiotics. "Resistance" means that the bacteria no longer respond to the antibiotic therapy. "Susceptibility" is a term used to describe how sensitive bacteria are in responding to antibiotic therapy. What some people call resistant may in fact be just "less susceptible."

Resistance to antimicrobials usually is a result of antimicrobial use. If you use them, resistance will likely, eventually, develop. Overuse and misuse of antibiotics may speed up the development of resistance. Long-term exposure to antibiotics allows resistant bacteria to be genetically "selected" from large populations which then pass the resistant gene on to future populations.

Some bacteria have natural, inherent resistance to antimicrobials and the genes for this resistance may reside together in small packets of their DNA. Science has discovered ways in which these resistant genes can be passed on from bacteria to bacteria within and even across species. David Reeves has addressed antimicrobial resistance in greater detail (see story beginning on page 36).

At Issue Opponents to their use don't argue the importance of antimicrobials in animal agriculture. They have also acknowledged their importance for sustainable livestock production and for the control of animal infections to protect public and animal health. They further recognize that misuse of antimicrobials in humans by physicians has been a major source of resistance development in human pathogens.

The main concern of these opponents is those antibiotics which have both agricultural and human applications. If resistance develops in animals, which could be transferred to humans, it could result in making the disease more difficult to treat in the human patient.

A relatively new, effective class of antimicrobials referred to as the fluoroquinolones is of special importance to the human medical community. Evidence of resistance in human pathogens is starting to emerge.

Although this class of antimicrobials has only recently received approval for therapeutic use in poultry and cattle in the U.S., this new class of antibiotics has been widely used in other parts of the world for human and veterinary purposes. These compounds are banned from extra-label use in all species of food animals in the U.S.

Subtherapeutic and growth promotant uses of antimicrobials (especially any antimicrobials which are being used for therapeutics in humans or even animals) are of primary concern to those organizations promoting judicious use. Calls for discontinuing subtherapeutic use of antimicrobials has been made as far back as 1969 and some European countries have adopted this policy.

In the U.S., the portion of the resistance issue which is receiving the most attention from the FDA's CVM surrounds the fluoroquinolones. Since the approval in poultry in 1997, and for bovine in 1998, there have been increased efforts toward monitoring of resistance. The resistance issue is holding up the approval process as FDA officials consider the potential effect on human health. The FDA-CVM must have "reasonable certainty of doing no harm" to human health before an antimicrobial can be approved. This "reasonable certainty" must also be applied to the resistance issue. This issue will make future approvals for any farm animal antibiotics, which are first approved for use in humans, very difficult. Mike Apley discusses the drug approval process in his story which begins on page 42.

Implications For Livestock With all the controversy swirling around food safety and antibiotic resistance issues of late, what are the real implications for animal agriculture, especially pork production?

I believe that we can observe what has happened in the European Union to get an idea of what the trend may be in the U.S. The major implications I see are:

The future approval of new therapeutic antimicrobials will certainty be slowed down as the FDA-CVM learns to come to grips with ways to address the resistance issue and its potential affect on human health.

Subtherapeutic use of any antibiotic, which is currently used therapeutically in humans, will eventually be evaluated and be put "on the table" for restricted use.

Over-the-counter (OTC) availability of antimicrobials of all kinds will receive increased scrutiny.

The extra-label use of antimicrobials will be accompanied with increased scrutiny and regulatory pressure.

All production enhancement antimicrobial use will be reviewed in light of experiences in other parts of the world and pressures from organizations such as WHO and our own CDC.

We will continue to develop production technologies which will leave us less dependent on the need for antimicrobials.

New and improved methods of surveillance and tracking will be developed. The result will be the ability to trace problems back to the farm of origin and eliminate repeat problem herds.

Use of antibiotics in the U.S. pork industry may become a barrier to free trade and product exports should we be unable to address these issues proactively.

Educational programs will be developed for veterinarians and producers alike that will promote prudent use of antimicrobials and reduce the likelihood of developing resistance.

Judicious, Therapeutic Use The American Veterinary Medical Association (AVMA) has funded a steering committee to develop basic guidelines of judicious antibiotic use. This committee has the charge of planning how to best disseminate this information throughout the various species groups. It will be essential for the various species groups to develop their own specific guidelines for use with producers, and then launch an educational effort to implement these guidelines. Following are the Judicious Use Principles as defined by the committee:

Preventive strategies, such as appropriate husbandry and hygiene, routine health examinations, and immunizations, should be emphasized.

Other therapeutic options should be considered before antibiotic therapy.

Judicious use of antimicrobials, when under the direction of a veterinarian, should meet all requirements of a valid, veterinarian-client-patient relationship.

Prescription, Veterinary Feed Directive (VFD), and extra-label use of antimicrobials must meet all the requirements of a valid, veterinarian-client-patient relationship.

Extra-label antibiotic therapy must be prescribed only in accordance with the Animal Medicinal Drug Use Clarification Act amendments to the Food, Drug and Cosmetic Act and its regulations.

Veterinarians should work with those responsible for the care of animals to use antimicrobials judiciously, regardless of the distribution system through which the antimicrobial was obtained.

Regimens for therapeutic, antimicrobial use should be optimized using current pharmacological information and principles.

Antimicrobials considered important in treating refractory infections in human or veterinary medicine should be used in animals only after careful review and reasonable justification. Consider using other antimicrobials for initial therapy.

In this context, this principle takes into account development of resistance or cross-resistance to important antimicrobials.

Use narrow-spectrum antimicrobials whenever appropriate.

Utilize culture and susceptibility results to aid in the selection of antimicrobials when clinically relevant.

Therapeutic antimicrobial use should be confined to proper clinical indications. Improper uses such as for uncomplicated viral infections should be avoided.

Therapeutic exposure to antimicrobials should be limited to treatments lasting only as long as needed to achieve the desired clinical response.

Consult records of treatment and outcome to evaluate therapeutic regimens.

What Should We Do? The development of Judicious Use Guidelines for pork production is in the works. Certainly, the continued development of a fundamental understanding of resistance by everyone involved with pork production is important, as is continued research and study of antimicrobial resistance. We must strive to assess the risks involved with continued use of antimicrobials.

Pork producers and veterinarians must work to assure that we are using antimicrobials properly and within the context of the judicious-use principles. We must understand that new approvals of antimicrobials may come with strings attached. That will force us to be more aware of the resistance issue and public health.

For instance, the VFD for the use of tilmicosin (Pulmotil) was an example of the types of increased controls that the regulators will require for new approvals. The VFD is just one case where regulations can be employed which encourage judicious use of antimicrobials.

There is no doubt that antibiotics and their use in animal agriculture have made a tremendous, positive impact on the quality and quantity of pork and the other meat protein products in the U.S. and around the world. We cannot let the emotionalism and sensationalism replace good science and judgment as we enter the next millennium. Antimicrobials have been a tremendous tool in the past and they promise to be even more important in the future as we attempt to meet the needs of a growing world population.

Antibiotic - a chemical substance produced by a microorganism which has the capacity, in dilute solutions, to inhibit the growth of or to kill other antimicrobials. Antimicrobial - an agent that kills bacteria or suppresses their multiplication or growth. This includes antibiotics and synthetic agents. This excludes ionophores and arsenicals.

Narrow-Spectrum Antimicrobial - an antimicrobial effective against a limited number of bacteria often applied to an antimicrobial active against either gram-positive or gram-negative bacteria.

Broad-Spectrum Antimicrobial - an antimicrobial effective against a large number of bacteria; generally describes antibiotics effective against both gram-positive and gram-negative bacteria.

Antibiotic Resistance - a property of bacteria that confers the capacity to inactivate or exclude antibiotics or a mechanism that blocks the inhibitory or killing effects of antibiotics.

Extra-label - Extra-label use means actual or intended use of a drug in an animal in a manner that is not in accordance with the approved labeling. This includes, but is not limited to, use in species not listed in the labeling, use for indications (disease or other conditions) not listed in the labeling, use at dosage levels, frequencies, or routes of administration other than those stated in the labeling, and deviation from the labeled withdrawal time based on these different uses.

Immunization - the process of rendering a subject immune or of becoming immune, either by conventional vaccination or exposure.

Monitoring - monitoring includes periodic health surveillance of the population or individual animal examination.

Veterinarian-Client-Patient Relationship (VCPR) - A VCPR exists when all of the following conditions have been met:

1. The veterinarian has assumed the responsibility for making clinical judgments regarding the health of the animal(s) and the need for medical treatment, and the client had agreed to follow the veterinarian's instructions.

2. The veterinarian has sufficient knowledge of the animal(s) to initiate at least a general or preliminary diagnosis of the medical condition of the animal(s). This means that the veterinarian has recently seen and is personally acquainted with the keeping and care of the animal(s) by virtue of an examination of the animal(s) or by medically appropriate and timely visits to the premises where the animal(s) are kept.

3. The veterinarian is readily available for followup evaluation, or has arranged for emergency coverage, in the event of adverse reactions or failure of the treatment regimen.

Veterinary Feed Directive (VFD) Drug - The VFD category of medicated feeds was created by the Animal Drug Availability Act of 1996 to provide an alternative to prescription status for certain therapeutic animal pharmaceuticals for use in feed. Any animal feed bearing or containing a VFD drug shall be fed to animals only by or upon a lawful VFD issued by a licensed veterinarian in the course of the veterinarian's professional practice.